Bioerodible polyester polymer implants and related methods of use

ABSTRACT

The present disclosure provides compositions that enable sustained release of a small molecule tyrosine kinase inhibitor, such as axitinib from a bioerodible polyester polymer implant for the treatment of disease. The composition is especially suitable for treating ophthalmic indications, such as neovascular age related macular degeneration and diabetic macular edema, by intravitreal injection of the implant. The implant is designed to be pre-loaded into a small diameter needle and injected via self-sealing scleral needle penetration at the pars plana. Small molecule tyrosine kinase inhibitors may be released from the implants over a period of one week to three years.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/855,666, filed May 31, 2019, and titled BIOERODIBLE POLYESTERPOLYMER IMPLANTS AND RELATED METHODS OF USE, which is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to implants for treating ocular diseases,such as neovascular age-related macular degeneration (nAMD) and diabeticmacular edema (DME), by intravitreal injection of the implant. Morespecifically, the implant includes a composition that enables thesustained release of a small molecule tyrosine kinase inhibitor (TKI),such as axitinib, from a bioerodible polyester polymer implant for thetreatment of disease.

BRIEF DESCRIPTION OF THE DRAWINGS

The written disclosure herein describes illustrative embodiments thatare non-limiting and non-exhaustive. Reference is made to certain ofsuch illustrative embodiments that are depicted in the figures, inwhich:

FIG. 1 is a chart exemplifying the effect of different co-monomer ratiosor molecular weights (MW) of PLGA or PLA on drug release and polymermatrix degradation for implant formulations.

FIGS. 2A and 2B are graphs of axitinib cumulative and daily in vitrorelease from a first formulation, according to one embodiment.

FIGS. 3A and 3B are graphs of axitinib cumulative and daily in vitrorelease from an eighth formulation, according to one embodiment.

FIGS. 4A and 4B are graphs of axitinib cumulative and daily in vitrorelease from a ninth formulation, according to one embodiment.

FIGS. 5A and 5B are graphs of axitinib cumulative and daily in vitrorelease from a tenth formulation, according to one embodiment.

FIG. 6 is a graph from a 60% axitinib-loaded polymer blend, according toone embodiment.

FIG. 7 is a graph from a 60% axitinib-loaded polymer blend according toa fifth formulation, according to one embodiment.

FIG. 8 is a graph of a release profile of TKI from a PLA/PLGA implantover a four week period.

FIG. 9A is a picture of an axitinib implant in the vitreous of a DutchBelted rabbit initially after implant.

FIG. 9B is a picture of an axitinib-loaded implant in the vitreous of aDutch Belted rabbit 50 days after implant.

FIG. 10 is a graph of the efficacy of an axitinib-loaded implant inpreventing leakage assessed by fluorescein angiography in the DL-AAAmodel of persistent retinal vascular leakage (1 Formulation 5 axitinibimplant=1a-AXT and 1 placebo implant=1b-TMCPlac). The y-axis representsa leakage score based on a predefined scale.

FIG. 11A is a fluorescein angiography of an axitinib implant beforeimplantation.

FIG. 11B is a fluorescein angiography of an axitinib implant two dayspost-implantation.

FIG. 11C is a fluorescein angiography of an axitinib implant 56 dayspost-implantation.

FIG. 11D is a fluorescein angiography of a placebo-loaded implant beforeimplantation.

FIG. 11E is a fluorescein angiography of a placebo-loaded implant twodays post-implantation.

FIG. 11F is a fluorescein angiography of a placebo-loaded implant 56days post-implantation.

DETAILED DESCRIPTION

From a drug delivery standpoint, the eye can be separated into anteriorand posterior segments. The anterior segment includes the lids,conjunctiva, cornea, aqueous humors, trabecular meshwork, iris, ciliarybody and lens. The posterior segment is made up of the uveal tract,vitreous humor, retina, retinal pigmented epithelium, and choroid.

Diseases of the anterior segment include conjunctivitis, dry eye andocular hypertension. Numerous disease states also affect the posteriorsegment of the eye and cause significant morbidity. These includeneovascular age-related macular degeneration (nAMD), uveitis,proliferative vitreal retinopathy, diabetic macular edema (DME), andretinal vein occlusion, amongst others. New pharmacologic agents arebeing developed that can be used to treat these diseases; however, theymust achieve therapeutic concentrations in the affected tissues to beeffective. Hence, for diseases of the vitreous, retina, choroid anduveal tract, a drug must reach the posterior segment.

The eye poses considerable challenges for both topical and systemicdelivery of drugs to the posterior segment. Topical delivery to theanterior segment of the eye is highly inefficient with typicalbioavailability of between 1% to 5%. Further movement from the anteriorchamber to the posterior segment is prevented by the iridolenticulardiaphragm. What little drug that enters the anterior-most portions ofthe posterior segment from topical delivery must also overcome a largediffusional barrier to reach the macula area of the eye. These hurdlesrender topical administration of drugs to the posterior segment mostlyineffective. In addition, the blood retinal barrier greatly minimizes orprevents systemic delivery to the posterior segment. Due to theseconstraints, most drugs used to treat posterior segment ophthalmicdiseases are administered by intravitreal administration.

Due to the barriers to absorption to the posterior segment of the eyeand the rapid vitreal clearance of most small molecules (<10 hours), themost effective route of drug administration is by multiple intravitrealinjections. Direct intravitreal injection is currently the route ofadministration for most retina drugs including Kenalog-40®, Triesence®,Eylea®, Avastin® and Lucentis® (ranibizumab injection). Multipleintraocular injections are required to maintain the therapeutic effectfrom these solution and suspension dosage forms. This carries the riskof poor patient compliance, intravitreal hemorrhages, retinal andvitreous detachment, cataract, and endophthalmitis. Sustained andcontrolled delivery directly into the vitreous addresses this problemand also tempers the potential high peak drug levels achieved throughfrequent pulsed dosing. For this reason, there is a very significantunmet medical need for sustained intraocular drug delivery systems.

Vascular endothelial growth factor (VEGF) has been implicated in retinalneovascularization, and inhibiting VEGF to treat exudative ophthalmicdiseases is clinically validated. Currently, bevacizumab (Avastin®),ranibizumab (Lucentis®) and aflibercept (Eylea®) are clinicallyeffective in treating nAMD and DME. These are macromolecular ligands forVEGF and work extracellularly. Small molecule tyrosine kinase inhibitors(TKIs) also inhibit VEGF, but act on intracellular targets. Hence, thesemolecules need to have the appropriate disposition to and into thetarget cells from their route of administration. Many of these compoundshave achieved significant clinical success in treating cancer. Axitinib(Inlyta®, Pfizer) is approved for the treatment of renal cell carcinomawith daily doses ranging up to 20 mg. Additionally, systemicadministration of axitinib to rats by an infusion pump inhibitedvascular leakage in a laser-induced rat choroidal neovascularizationmodel. However, direct intraocular administration would be required totreat retinal diseases to prevent systemic side effects from a smallmolecule tyrosine kinase inhibitor.

Treatment of nAMD or DME with small molecule tyrosine kinase inhibitors(TKIs) has not met with success so far. Several preclinical studies andclinical studies have assessed TKIs for the treatment of retinalvascular leakage by many routes of administration: topical drops,systemic administration, intravitreal injection of suspensions andintravitreal injection of polymeric TKI microparticles. Topicaladministration of small molecule TKIs has not been shown to achieveclinically significant concentrations of the TKI at the macula.Additionally, significant non-productive absorption into the systemiccirculation occurs with topical dosing leading to significant potentialside effects. Systemic dosing of TKIs also carries the significantpotential for off-target effects and severe adverse events. It has beenshown that most particulate dosage forms, suspensions or sustainedrelease microparticles are not well tolerated in the back of the eyecausing retinal inflammation, traction retinal detachment, adherence ofthe particulates to the lens and migration of the particles into theanterior chamber. The exception to this are steroids, such astriamcinolone acetonide.

The components of the embodiments as generally described and illustratedin the figures herein can be arranged and designed in a wide variety ofdifferent configurations. Thus, the following more detailed descriptionof various embodiments, as represented in the figures, is not intendedto limit the scope of the present disclosure, but is merelyrepresentative of various embodiments. While various aspects of theembodiments are presented in drawings, the drawings are not necessarilydrawn to scale unless specifically indicated.

The present disclosure provides compositions that enable the sustainedrelease of a small molecule TKI, such as axitinib, from a bioerodiblepolyester polymer implant for the treatment of disease. The compositionis especially suitable for treating ophthalmic indications such as nAMDand DME by intravitreal injection of the implant. The implant isdesigned to be pre-loaded into a small-gauge needle and injected viaself-sealing scleral needle penetration at the pars plana. Smallmolecule TKI, such as axitinib, may be released from the implant invitro or in vivo over a period of one week to three years.

The present disclosure also provides an intravitreal implant that isconfigured to be delivered to or implanted into an eye of a subject or apatient. The intravitreal implant may release a therapeutic agent into avitreous humor of the eye of the subject at an effective rate for atleast six months. The intravitreal implant may release the therapeuticagent and may release the therapeutic agent for at least one year fromimplantation.

The implant may include a bioerodible polyester polymer blend and atherapeutic agent. The therapeutic agent may be a small moleculetyrosine kinase inhibitor (TKI). The TKI may be selected from at leastone of axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib,sunitinib, tivozanib, lentvatinib, and the like. The effective rate ofrelease of the TKI may range from about 10 ng/day to about 10 mg/day.

In some embodiments, after implantation, there may be an initial burstrelease phase during which time the therapeutic agent is released fromthe polymer at a rate faster than the substantially constant rate itsubsequently maintains for a period of time. The burst release phase canvary in length between a few minutes and several days depending on thetherapeutic agent and the polymer matrix. In some embodiments, the burstrelease of therapeutic agent from the composite implant may be less thanabout 10% (w/w) during the burst release phase. In certain embodiments,the burst release of therapeutic agent from the composite implant may beless than about 9% (w/w), less than about 8% (w/w), less than about 7%(w/w), less than about 6% (w/w), less than about 5% (w/w), less thanabout 4% (w/w), less than about 3% (w/w), less than about 2% (w/w), orless than about 1% (w/w) during the burst release phase. In otherembodiments, the burst release of therapeutic agent from the compositeimplant may be less than about 1% (w/w) during the burst release phase.For example, in some embodiments, the burst release of the therapeuticagent form the composite implant may be less than about 10% (w/w) overan initial 24-hour period from implantation in an eye of a patient. Inother embodiments, the burst release of the therapeutic agent form thecomposite implant may be less than about 1% (w/w) over an initial24-hour period from implantation in an eye of a patient. The phrases“from implantation” and “after implementation” may be usedinterchangeably.

The release rate of the therapeutic agent from the implant may besubstantially constant. In some embodiments, the release rate of the TKIfrom the implant is substantially constant over an initial three-monthperiod from implantation beginning with the end of the burst release orlag phase, but not more than approximately 14 days post-implantation orinitiation of in vitro release studies. In some embodiments, the releaserate of the TKI from the implant is substantially constant over aninitial three-month period from implantation beginning with the end ofthe burst release or lag phase, but not more than approximately 28 dayspost-implantation or initiation of in vitro release studies. The lagphase is defined as the period immediately post-implantation orimmediately after initiating in vitro release studies where no drug isreleased or the drug is released at a slower rate than the constant rateachieved after not more than 14 days.

The release rate of the therapeutic agent from the implant may benear-zero order or pseudo-zero order over some period of time. Incertain embodiments, the release rate of the TKI from the implant isnear-zero order or pseudo-zero order over an initial three-month periodfrom implantation beginning with the end of the burst release or lagphase, but not more than 14 days post-implantation or initiation of invitro release studies. Near-zero order release and pseudo-zero orderrelease kinetics are defined as an essentially linear relationship ofthe cumulative amount of therapeutic agent released from the implant invivo or in in vitro release studies as a function of time.

The bioerodible polyester polymer blend may comprise a plurality ofdifferent polyester polymers. Exemplary polyester polymers may includepoly(glycolic acid) (PGA), poly(lactic acid) (PLA), and the copolymerpoly(lactic-co-glycolic acid) (PLGA). These polymers have been used withconsiderable success in the clinic as suture materials, as orthopedicfixation devices, and for drug delivery. Some examples of approved andcommercialized drug delivery systems comprising PLA/PLGA polymersinclude: Nutropin® Depot (human growth hormone), Sandostatin LAR®(octreotide), Trelstar® Depot (triptorelin pamoate), and Zoladex®(goserelin acetate).

Therapeutic agent delivery systems comprised of PLA/PLGA can bemanufactured by various means as microparticles with therapeutic agentsdispersed within, extruded as polymeric implants from a drug polymerblend, formed into core/shell implants with the PLA/PLGA as an outershell or coating and an inner drug matrix core, formed into tablets,wafers or implants by compression molding of drug polymer blends andother morphologies and dosage forms. A therapeutic agent may be releasedfrom a PLA/PLGA drug matrix by means of diffusion from the polymerdelivery system. This proceeds by hydration of the implant along withconcurrent erosion of the polymer chains and diffusion of the drug outof the system.

The rate of the therapeutic agent release and polymer erosion iscontrolled by many factors including therapeutic agent solubility,particle size, domain size, lipophilicity and crystallinity as well aspolymer co-monomer ratio, crystallinity, molecular weight (MW), endgroup (ester or acid), residual monomers and solvents, manufacturingprocesses, and porosity and density of the dosage form. In general,crystalline polymers have a slower release of drug and longer erosiontime. The higher the lactic acid content of the polymer, the slower thedrug release and the longer the polymer erosion time. The higher the MWof the polymer, the longer the release and the longer the erosion time.Acid end group polymers will erode faster than aliphatic ester end grouppolymers.

The polymers and polymer blends must be engineered with thephysicochemical properties of the drug in mind, the therapeutic target,the release rate, and the need for timely polymer erosion. The site ofimplantation is also a key factor. The posterior segment of the eye isparticularly sensitive to foreign bodies and chemical insults. A balanceof compound physicochemical properties and the polymer properties isrequired to optimize drug release, polymer erosion, and oculartolerability. Excessive burst release, long lag times and erosion timesthat greatly exceed the drug release from the implant must be avoided.

In some embodiments, the bioerodible polyester polymer blend maycomprise of at least two polymers. For example, the implant may comprisean acid or ester end group PLA and an acid or ester end group PLGA,wherein at least one of the polymers comprises an ester end group.

In certain embodiments, the bioerodible polyester polymer blendcomprises two polymers. In particular embodiments, the ratio of PLA toPLGA may range from between about 10:1 to about 1:10. In otherembodiments, the ratio of PLA to PLGA may range from between about 9:1to about 1:9. In certain other embodiments, the ratio of PLA to PLGA mayrange from between about 8:1 to about 1:8. In further embodiments, theratio of PLA to PLGA may range from between about 7:1 to about 1:7. Inyet another embodiment, the ratio of PLA to PLGA may range from betweenabout 6:1 to about 1:6. In particular embodiments, the ratio of PLA toPLGA may range from between about 5:1 to about 1:5. In anotherembodiment, the ratio of PLA to PLGA may range from between about 4:1 toabout 1:4.

The PLA polymer of the implant may be selected from polymers with aninherent viscosity selected from between about 0.16 dl/g to about 0.35dl/g, as measured in 0.1% chloroform (25° C., Ubbelohde) size 0capillary viscometer.

The PLGA polymer of the implant may be selected from polymers withlactide to glycolide ratios that range from between about 50:50 to about85:15. The PLGA polymers may have an inherent viscosity ranging frombetween about 0.16 dl/g to about 1.0 dl/g.

The polyester polymer blend may comprise an ester end group PLGA with alactide to glycolide ratio that ranges from between about 75:25 andabout 85:15 with a viscosity that may be greater than about 0.32 dl/gand an acid or ester end group PLGA with a viscosity that may range frombetween about 0.16 dl/g and about 1.0 dl/g.

The implant may be fabricated in a number of different ways. Forexample, the implant may be extruded, injection molded, compressionmolded, or solvent cast. Various other methods of making or fabricatingthe implants are also within the scope of this disclosure.

The implant may be introduced, implanted, or delivered into an eye of asubject or patient. For example, the implant may be injected into avitreous humor of a subject via a self-sealing scleral needlepenetration at the pars plana. The needle may be less than about 19gauge, less than about 20 gauge, less than about 21 gauge, less thanabout 22 gauge, less than about 25 gauge, or other appropriate diameter.In some embodiments, the needle is a 21 gauge or smaller diameterneedle. In certain embodiments, the needle is a small diameter needle,or a needle with a gauge number greater than 21.

The present disclosure also provides methods related to the use ofintravitreal implants. In certain embodiments, the present disclosureprovides methods of introducing a therapeutic agent into an eye of asubject or a patient. Such methods comprise delivering an implant to asdescribed above into an eye of a subject. In other embodiments, thepresent disclosure provides methods of treating an ocular disease in asubject that comprise delivering an implant as described above to an eyeof the subject. The ocular disease may be selected from at least one ofneovascular age related macular degeneration and diabetic macular edema.

The present disclosure also provides for therapeutic agents for use intreating an ocular disease, wherein the therapeutic agent is provided inan implant as described above. Furthermore, the present disclosureprovides for use of a therapeutic agent in the manufacture of an implantas described above for treatment of a subject in need thereof. Thepresent disclosure also provides a pre-loaded injector assemblycomprising a needle and an implant as described above.

EXAMPLES

To further illustrate these embodiments, the following examples areprovided. These examples are not intended to limit the scope of theclaimed invention, which should be determined solely on the basis of theattached claims.

The desired release rate of axitinib from an intraocular implant wasdetermined from the IC₅₀ of the compound. It is assumed that anintravitreal implant must deliver a therapeutic concentration in thevitreous at least 100 fold higher than its IC₅₀ to be effective. Thisallows for a diffusion gradient to be established across the posteriorsegment of the eye. This diffusional gradient can sometimes result in a10 fold drop in vitreous drug concentration from an implant to theretina. An additional 10 fold level above the 10×IC₅₀ is required toaccommodate penetration across the retinal pigment epithelium RPE andinto the affected cells as tyrosine kinases are intracellular targets.Hence, the target vitreous concentration was estimated to be 100× thecellular IC₅₀ of the compound.

The drug must also have sufficient solubility to support a diffusionalrelease from the implant into the vitreous. Compounds diffuse against aconcentration gradient. If the concentration in the vitreous equals thesolubility of the compound, there is no driving force for diffusion andrelease from the implant will be stopped.

Based on this, it is anticipated that a vitreous concentration of 7.7ng/mL is needed for axitinib. The solubility supports this allowing fordiffusion from the implant. Assuming a vitreous half-life for axitinibof two hours, 256 ng/day would be needed for efficacy for a 4 mL volume.Many TKIs do not have a solubility/potency ratio that supportsestablishing the required concentration gradients. Pazopanib, forexample, can only achieve a concentration of 10× its IC₅₀ as seen inTable 1.

TABLE 1 Select TKI required release rates for intravitrealadministration. Compound IC50/EC50 100x = Cvit Aq. Sol Release rateAxitinib 0.2 nM 7.7 ng/mL 0.2 ug/mL 256 ng/day Pazopanib  30 nM 1.3ug/mL 3.3 ug/mL  32 μg/day

A design of experiments was set up to identify the design space for theaxitinib formulations. Different PLA and PLGA polymers whosecharacteristics are given in Table 2 were used to formulate the axitinibimplants according to the matrix in Table 3. These included the EvonikResomers R202S and R203S (high and low MW PLA, ester end group), RG502and RG503 (high and low MW 50:50 PLA:PGA copolymer, ester end group),RG752H (acid end group 75:25 PLA:PGA copolymer) and RG756S (high MW,ester end group 75:25 PLGA). The polymers were chosen to evaluate theeffects of MW, co-monomer ratio, and end group on drug release andpolymer erosion as depicted in

FIG. 1. The chart in FIG. 1 describes various polymer matrixes of PLAand PLGA. The higher the molecular weight of the PLA and PLGA, therelease duration increased and the matrix degradation increased. Thedifferent shading in the chart refers to release duration, a 1-3 monthrelease duration, a 3-12 month duration, or a greater than 12 monthduration.

TABLE 2 Characteristics of PLA polymers and PLGA polymers. Molec- GlassInherent ular Transition Ester End PLA or PLGA Polymer viscosity WeightTempera- or Acid (lactide to Type (dl/g) (kDa) ture (° C.) End glycolideratio) R203S 0.25-0.35 18-28 46-50 Ester End PLA R202S 0.16-0.24 10-1838-42 Ester End PLA RG756S 0.71-1.0   76-115 49-55 Ester End PLGA 75:25RG752H 0.14-0.22  4-15 42-46 Acid End PLGA 75:25 RG503 0.32-0.44 24-3844-48 Ester End PLGA 50:50 RG502 0.16-0.24  7-17 42-46 Ester End PLGA50:50 RG753S 0.32-0.44 PLGA 75:25 RG505 0.61-0.74 54-69 48-52 Ester EndPLGA 50:50

Weights of polymers are given in mg.

The formulations were manufactured by first milling the axitinib drugsubstance and the PLA and PLGA polymers using a jet mill. This allowedfor consistent particle size reduction of the starting materials. Thepolymers were then mixed with axitinib according to the matrix in Table3. Each mixture was then heated above its glass transition temperatureto form a viscous dough. The dough was mixed to achieve a homogeneousdispersion of axitinib in the blend. Once mixed, the dough was heatcompressed on a specially designed press. The heat pressed axitinib/PLGAwafers were then cut into individual implants.

Release of the axitinib from the implants was assessed in vitro.Implants were placed into 50 mL polypropylene vials containing 45 mL ofisotonic saline at pH 7.4 as the release media. The vials were thenplaced on a shaker bath to agitate the medium at 37° C. Atpre-determined timepoints the media was sampled and the entire receivermedia was replaced with fresh saline. The axitinib concentration in thesampled aliquot was quantified by High Performance Liquid Chromatography(HPLC) using a Waters Alliance e2695 system with a C-18 Hypersil ODScolumn. The axitinib concentrations were used to define the cumulativein vitro release of axitinib from the implant as well as the dailyaxitinib release rate.

A summary of the release results for formulations 1 through 10 with a60% axitinib load in the design matrix from Table 3 is provided below.The 40% loaded axitinib implants released similarly to their 60%counterparts. Representative release profiles are depicted in FIGS. 2Athrough 5B. In summary, all implants manufactured with a single PLGApolymer except 756S erode within nine to 12 weeks and are not suitablefor a six-month implant. Implants manufactured with a single PLA polymeror the 756S polymer released at sub-therapeutic rates and may notbioerode for years. However, axitinib implants manufactured fromspecific blends of a PLA and a PLGA demonstrated promising releaseprofiles.

Formulation 1: (R2025; PLA) 60% axitinib load, 1% burst release then 3%released over 14 weeks. The release rate was marginally therapeutic at60 days.

Formulation 2: (R2035; PLA) 60% axitinib load, 1.5% burst then 3%released over 14 weeks. The release rate was sub-therapeutic after theburst out to 13 weeks.

Formulations 3-5: (RG502, RG503, RG752H; PLGAs) 60% axitinib load, 5%was released in eight weeks, but the implants fall apart between nineand 12 weeks.

Formulation 6: (RG756S; high MW PLGA) 60% axitinib load, sub-therapeuticrelease rate after initial burst for 11 weeks. 11 to 13 weekstherapeutic. 3.5% at 14 weeks.

Formulation 7: (R203S:RG756S) 60% axitinib load. Linear release, butonly 2% released over 13 weeks.

Formulation 8: (R202S:RG756S) 60% axitinib load. Lag for three weeksthen therapeutic. 6% released over 13 weeks.

Formulation 9: (R203S:RG503) 40% axitinib load. 6% over 20 weeks,four-week lag then therapeutic release rate achieved.

Formulation 10: (R203S:RG752H) 60% axitinib load. 5% over 13 weeks. Nolag and marginally therapeutic release rate out to four weeks.

FIGS. 2A and 2B are graphs of axitinib cumulative and daily in vitrorelease from the first formulation. FIG. 2A illustrates the percenteluted over time (for three samples) and FIG. 2B illustrates the elutionrate in ng/mg/day (of one sample).

FIGS. 3A and 3B are graphs of axitinib cumulative and daily in vitrorelease from the eighth formulation. FIG. 3A illustrates the percenteluted over time (for three samples) and FIG. 3B illustrates the elutionrate in ng/mg/day (of one sample).

FIGS. 4A and 4B are graphs of axitinib cumulative and daily in vitrorelease from the ninth formulation. FIG. 4A illustrates the percenteluted over time (for three samples) and FIG. 4B illustrates the elutionrate in ng/mg/day (of one sample).

FIGS. 5A and 5B are graphs of axitinib cumulative and daily in vitrorelease from the tenth formulation. FIG. 5A illustrates the percenteluted over time (for three samples) and FIG. 5B illustrates the elutionrate in ng/mg/day (of one sample).

Implant formulations comprising blends of PLA and PLGA were chosen foroptimization. Specifically, the following blends were evaluated:R203S:RG752H and R202S:RG503. For each blend, the ratio of PLA to PLGAwas varied from 1:1 to 1:2 and 1:3, with increasing PLGA content.Implants containing 60% axitinib were manufactured with the polymerblends by hot melt compression as described above. The release ofaxitinib was determined as described above. The optimization yieldedformulations that display a linear release with minimal burst or lagtime and meet the release criteria and are expected to erode in a timelyfashion. The release profile of an exemplary sample is depicted in FIG.6 (three samples of R202S:RG503, PLA to PLGA ratio 1:3, 60% axitinibload).

A three month intravitreal tolerability study with axitinib/PLGA wasconducted in Dutch Belted (DB) and New Zealand White rabbits.Axitinib-loaded and placebo implants were well-tolerated out to day 90based on ophthalmic examination.

Formulation 5 from the original design of experiments was chosen for thetolerability and efficacy studies. The slowly increasing rate ofaxitinib release from Formulation 5 enabled the tolerability andefficacy as a function of release rate to be determined. The in vitrorelease of axitinib from formulation 5 (RG752H) is shown in FIG. 7 (forthree samples).

FIG. 8 illustrates a mean release profile of TKI from an optimizedPLA/PLGA implant over a period of four weeks (three samples ofR202S:RG503, PLA to PLGA ratio 1:3, 60% axitinib load). The burstrelease of the TKI is less than 1% after an initial 24-hour period afterimplantation. In fact, the percent release of TKI is less than 1% aftera week and a half post-implantation.

Formulation 5 displays no lag time, rapidly approaches the anticipatedeffective axitinib release rate of 256 ng/day, and slowly increases therelease rate. Furthermore, the implant begins to degrade in vitro atabout 12 weeks with softening occurring around 10 weeks. FIG. 9A depictsthe implant in the eye of a DB rabbit initially, and FIG. 9B depicts theimplantation 60 days after implantation. This shows clear hydration andthe beginnings of implant erosion at day 60. Hence, the in vitro erosionrate correlated well with the in vivo erosion rate.

Axitinib intravitreal implants were evaluated in a translation model ofpersistent retinal vessel leakage following a single intravitrealinjection. The model is created by injecting DL-alpha-aminoadipic acidinto the vitreous of DB rabbits. The model produces a persistent retinalvascular leakage that responds to anti-VEGF treatment. Retinal leakageis monitored by fluorescein angiography. The model was validated using a2-mg injection of the commercial Eylea® (aflibercept) product. Eylea®(aflibercept) reduced the “leakage score” by 10 to 20 from baseline andlasted approximately two months as expected, matching the clinicalperformance. One axitinib implant inhibited fluorescein angiographyleakage similar to Eylea® (aflibercept) for up to 115 days. The placebohad no effect on the leakage score. FIG. 10 depicts the leakage scoresnormalize to baseline values of axitinib compared to a placebo. FIGS.11A-11C show the fluorescein angiography of the axitinib implant atbefore implantation, two days after implantation, and 56 days afterimplantation. FIGS. 11D-11F show the fluorescein angiography of theplacebo implant before implantation, two days after implantation, and 56days after implantation.

Any methods disclosed herein include one or more steps or actions forperforming the described method. The method steps and/or actions may beinterchanged with one another. In other words, unless a specific orderof steps or actions is required for proper operation of the embodiment,the order and/or use of specific steps and/or actions may be modified.Moreover, sub-routines or only a portion of a method described hereinmay be a separate method within the scope of this disclosure. Statedotherwise, some methods may include only a portion of the stepsdescribed in a more detailed method.

Reference throughout this specification to “an embodiment” or “theembodiment” means that a particular feature, structure, orcharacteristic described in connection with that embodiment is includedin at least one embodiment. Thus, the quoted phrases, or variationsthereof, as recited throughout this specification are not necessarilyall referring to the same embodiment.

Similarly, it should be appreciated by one of skill in the art with thebenefit of this disclosure that in the above description of embodiments,various features are sometimes grouped together in a single embodiment,figure, or description thereof for the purpose of streamlining thedisclosure. This method of disclosure, however, is not to be interpretedas reflecting an intention that any claim requires more features thanthose expressly recited in that claim. Rather, as the following claimsreflect, inventive aspects lie in a combination of fewer than allfeatures of any single foregoing disclosed embodiment. Thus, the claimsfollowing this Detailed Description are hereby expressly incorporatedinto this Detailed Description, with each claim standing on its own as aseparate embodiment. This disclosure includes all permutations of theindependent claims with their dependent claims.

Recitation in the claims of the term “first” with respect to a featureor element does not necessarily imply the existence of a second oradditional such feature or element. It will be apparent to those havingskill in the art that changes may be made to the details of theabove-described embodiments without departing from the underlyingprinciples of the present disclosure.

We claim:
 1. An implant comprising: a tyrosine kinase inhibitor; and abioerodible polyester polymer blend, wherein the tyrosine kinaseinhibitor is present in the implant in an amount selected from a rangeof between about 5 and about 80 percent (w/w).
 2. The implant of claim1, wherein the tyrosine kinase inhibitor is present in the implant in anamount selected from a range of between about 40 to about 80 percent(w/w).
 3. The implant of claim 1, wherein the tyrosine kinase inhibitoris selected from a group consisting of axitinib, dasatinib, erlotinib,imatinib, nilotinib, pazopanib, tivozanib, lentvatinib and sunitinib. 4.The implant of claim 1, wherein the tyrosine kinase inhibitor isaxitinib.
 5. The implant of claim 1, wherein the bioerodible polyesterpolymer blend comprises at least two polymers.
 6. The implant of claim5, wherein the bioerodible polyester polymer blend comprises an acid orester end group polylactic acid (PLA) and an acid or ester end grouppoly-D,L-lactide-co-glycolide (PLGA), and wherein at least one of thepolymers comprises an ester end group.
 7. The implant of claim 6,wherein the PLA is selected from polymers with an inherent viscosityselected from between about 0.16 dl/g to about 0.35 dl/g as measured in0.1% chloroform (25° C., Ubbelohde) size 0 capillary viscometer.
 8. Theimplant of claim 6, wherein the PLGA is selected from polymers withlactide to glycolide ratios selected from between about 50:50 to about85:15, and wherein the PLGA is selected from polymers with an inherentviscosity selected from between about 0.16 dl/g to about 1.0 dl/g. 9.The implant of claim 1, wherein the bioerodible polyester polymer blendcomprises an ester end group poly-D,L-lactide-co-glycolide (PLGA) with a75:25 or 85:15 lactide to glycolide ratio and an inherent viscosity ofgreater than about 0.32 dl/g and an acid or ester end group PLGA with aninherent viscosity selected from between about 0.16 dl/g to about 1.0dl/g.
 10. The implant of claim 6, wherein the ratio of PLA to PLGA isselected from a range of between about 10:1 to about 1:10, a range ofbetween about 9:1 to about 1:9, a range of between about 8:1 to about1:8, a range of between about 7:1 to about 1:7, a range of between about6:1 to about 1:6, a range of between about 5:1 to about 1:5, or a rangeof between about 4:1 to about 1:4.
 11. The implant of claim 10, whereinthe ratio of PLA to PLGA is selected from a range of between about 4:1to about 1:4.
 12. The implant of claim 1, wherein the release rate ofthe tyrosine kinase inhibitor from the composite implant is selectedfrom a range of between about 10 ng/day to about 10 mg/day.
 13. Theimplant of claim 1, wherein the implant releases the tyrosine kinaseinhibitor for at least six months from implantation in a vitreous humorof an eye of a subject.
 14. The implant of claim 1, wherein the implantreleases the tyrosine kinase inhibitor for at least one year fromimplantation in a vitreous humor of an eye of a subject.
 15. The implantof claim 1, wherein a burst release of the tyrosine kinase inhibitorfrom the implant is less than 10 percent (w/w) over an initial 24-hourperiod from implantation in an eye of a subject.
 16. The implant ofclaim 1, wherein a burst release of the tyrosine kinase inhibitor fromthe implant is less than 1 percent (w/w) over an initial 24-hour periodfrom implantation in an eye of a subject.
 17. The implant of claim 1,wherein the release rate of the tyrosine kinase inhibitor from theimplant is substantially constant over an initial three-month periodfrom implantation beginning with the end of the burst release or lagphase, but not more than 14 days post-implantation.
 18. The implant ofclaim 1, wherein the release rate of the tyrosine kinase inhibitor fromthe implant is near-zero order or pseudo-zero order over an initialthree-month period from implantation beginning with the end of the burstrelease or lag phase, but not more than 14 days post-implantation.
 19. Amethod of introducing a tyrosine kinase inhibitor into an eye of asubject, comprising: injecting an implant into a vitreous humor of aneye of a subject, the implant comprising: the tyrosine kinase inhibitor;and a bioerodible polyester polymer blend, wherein the tyrosine kinaseinhibitor is present in the implant in an amount selected from a rangeof between about 5 and about 80 percent (w/w).
 20. A pre-loaded injectorassembly comprising: a needle; and an implant comprising: a tyrosinekinase inhibitor; and a bioerodible polyester polymer blend, wherein thetyrosine kinase inhibitor is present in the implant in an amountselected from a range of between about 5 and about 80 percent (w/w), andwherein the implant is loaded in the needle.